I. Field of the Invention
The present invention relates to fields of chemistry and cell biology generally, and more specifically, to the preparation of psorospermin and psorospermin analogs, and their use as tumor inhibitors.
II. Brief Description of the Prior Art
During the last 20 years, significant advances have been made in elucidating the molecular mechanisms responsible for selective antitumor activity of antitumor agents that target DNA. For example, it is now known that adriamycin is a topoisomerase II poison, that topotecan is a topoisomerase I poison, and that cis-Pt cross-links DNA and may express its selectivity by sequestering or hijacking DNA binding proteins. More recently, signaling pathways leading to apoptosis were uncovered, and the importance of p53 status and the involvement of a multitude of other signaling molecules were inferred. Downstream effectors have become important modulators of antitumor activity, and more specific therapeutic strategies are envisioned using cytostatic agents, differentiation agents, and telomerase inhibitors. These approaches are still experimental, but they hold much hope for a gentler form of cancer treatment.
One promising compound that has been shown to down-regulate downstream effector pathways involving anti-apoptotic factors is psorospermin. Psorospermin is a cytotoxic dihydrofuranoxanthone. Optically active (−) psorospermin is isolated from the roots and stembark of the African plant psorospermum febrifugum. Psorospermin is mechanistically related to the pluramycin family of antitumor antibotics, and has been shown to exhibit significant activity in vitro against various tumor cell lines and in vivo against P388 mouse leukemia (Cassady et al., 1990; Kupchan et al., 1980; Kwok et al., 1998).
Psorospermin is particularly intriguing as an anticancer agent because it has low reactivity and poor sequence selectivity toward duplex DNA in comparison to similar compounds such as pluramycins, but at least equal in vitro cytotoxicity and a much more interesting profile in the NCI 60-panel screen (NCI Developmental Therapeutics Web Site). It is believed that a selectivity trigger must exist in vitro, and a variety of suggestions have been made, including DNA-protein cross-links as a consequence of psorospermin-induced abasic sites and topoisomerase I or II as potential cross-linking proteins (Permana et al., 1994).
Unfortunately, optically active (−) psorospermin is no longer readily available from its natural plant source in Africa. Additionally, there are no known methods of synthesizing psorospermin in usable quantities. A need therefore exists for methods of synthesizing psorospermin and psorospermin analogues.